The present invention relates to amide-type triazole compounds which have excellent antifungal activity or pharmacologically acceptable prodrugs thereof or salts thereof; to medicaments (particularly antifungal agents) containing these compounds as active ingredients; to pharmaceutical compositions for treatment of fungal infections which contain these compounds; to the use of these compounds in the manufacture of medicaments (particularly antifungal agents); and to a method for the prevention or treatment of fungal infections which comprises administering these compounds to a warm-blooded animal (particularly a human) in need thereof.
A lot of triazole-type compounds have been known as agents for the treatment of fungal infections in a human or animal. One of the most popular triazole-type compounds is fluconazole. However there have been fungal infections which cannot be clinically treated with fluconazole and there is a need for further compounds having more excellent antifungal activity.
Similar compounds to those of the present invention are disclosed in Japanese Patent Application Publication Nos. Hei-8-333350, Hei-10-279567 and Hei-11-80135.
The present inventors have made a great effort to find compounds having an excellent antifungal activity and found that the compounds of formula (I) (hereinafter referred to as compounds (I)) and pharmacologically acceptable prodrugs thereof and salts thereof exhibit excellent antifungal activity. Thereby the present invention has been completed.
The present invention relates to:
(1) an amide-type triazole compound (I) or a pharmacologically acceptable prodrug thereof or a salt thereof: 
xe2x80x83wherein:
Ar1 represents a phenyl group or a phenyl group substituted with 1 to 3 substituents (said substituents are selected from a halogen atom and a trifluoromethyl group);
Ar2 represents a phenylene group, a phenylene group substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom and a chlorine atom), a naphthylene group or a naphthylene group substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom and a chlorine atom);
X represents a sulfur atom or a methylene group;
R1 represents a hydrogen atom or a C1-3 alkyl group;
R2 represents a hydrogen atom or a C1-3 alkyl group;
R3 represents a C6-10 aryl group, a C6-10 aryl group substituted with 1 to 5 substituents selected from substituent group A, a heteroaryl group, a heteroaryl group substituted with 1 or 2 substituents selected from substituent group A, a C7-14 aralkyl group, and a C7-14 aralkyl group substituted with 1 to 5 substituents selected from substituent group A;
substituent group A comprises a C1-6 alkyl group, a C1-6 alkyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group), a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group), a C1-6 alkanoyl group, a C2-6 alkanoyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group), a C1-6 alkanoyloxy group, a C2-6 alkanoyloxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group), a halogen atom, a hydroxyl group, an amino group, a mercapto group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group, a group of formula xe2x80x94S(O)nR4 (wherein R4 represents a C1-6 alkyl group or a C1-6 alkyl group substituted with 1 to 5 substituents (said substituents are selected from halogen atoms), and n represents 0, 1, or 2), a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group and a (C3-6 cycloalkyl)C1-6 alkyl group; and
(2) a medicament containing an amide-type triazole compound or a pharmacologically acceptable prodrug thereof or a salt thereof described in (1) as an active ingredient.
In the above description:
The xe2x80x9chalogen atomxe2x80x9d in the definitions of the substituent of Ar1 and the substituent group A is, for example, a fluorine, chlorine, bromine and iodine atom; preferably a fluorine or chlorine atom; and most preferably a fluorine atom.
The xe2x80x9cC1-3 alkyl groupxe2x80x9d in the definitions of R1 and R2 is a straight or branched chain alkyl group having 1 to 3 carbons, for example, a methyl, ethyl, propyl or isopropyl group; preferably a methyl or ethyl group; and most preferably a methyl group.
The xe2x80x9cC6-10 aryl groupxe2x80x9d in the definition of R3 is an aromatic hydrocarbon group having 6 to 10 carbons, for example a phenyl, indenyl or naphthyl group, preferably a phenyl group.
The xe2x80x9cheteroaryl groupxe2x80x9d in the definition of R3 is a monocyclic aromatic heterocyclyl group or a fused aromatic heterocyclyl group. The xe2x80x9cmonocyclic aromatic heterocyclyl groupxe2x80x9d is a 5- or 6-membered aromatic heterocyclyl group containing 1 to 4 nitrogen, oxygen or sulfur atoms, for example, a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazyl group; preferably pyridyl or thiazolyl. The xe2x80x9cfused aromatic heterocyclyl groupxe2x80x9d is a 5- or 6-membered aromatic heterocyclyl group which contains 1 to 4 nitrogen, oxygen or sulfur atoms and is fused to 1 or 2 benzene rings or to 5- or 6-membered aromatic heterocyclyl groups containing 1 to 4 nitrogen, oxygen or sulfur atoms. Examples of such a fused heterocyclyl group include isobenzofuranyl, chromenyl, xanthenyl, phenoxathynyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl and benzothiazolyl; preferably benzothiazolyl.
A preferred heteroaryl group is a 5- or 6-membered aromatic heterocyclyl group having 1 or 2 nitrogen, oxygen or sulfur atoms or a bicyclic heterocyclyl group which is a 5- or 6-membered aromatic heterocyclyl group that has 1 or 2 nitrogen, oxygen or sulfur atoms and is fused to a benzene ring. A more preferred heteroaryl group is a furyl, thienyl, pyridyl, isoxazolyl, thiazolyl or benzothiazolyl group; and most preferred is a pyridyl, thiazolyl or benzothiazolyl group.
The xe2x80x9cC7-14 aralkyl groupxe2x80x9d in the definition of R3 is a C1-4 alkyl group substituted with a C6-10 aryl group. The xe2x80x9cC6-10 aryl groupxe2x80x9d has the same meaning as described above. The xe2x80x9cC1-4 alkyl groupxe2x80x9d is a straight or branched chain alkyl group having 1 to 4 carbons, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl group; preferably a methyl or ethyl group and most preferably a methyl group. The xe2x80x9cC7-14 aralkyl groupxe2x80x9d is, for example, a benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, or naphthylbutyl group; preferably a benzyl or phenethyl group and more preferably a benzyl group.
In addition the aryl ring of the xe2x80x9cC6-10 aryl groupxe2x80x9d and the xe2x80x9cC7-14 aralkyl groupxe2x80x9d in the definition of R3 is optionally substituted with 1 to 5 substituents selected from substituent group A and the xe2x80x9cheteroaryl groupxe2x80x9d in the definition of R3 is optionally substituted with 1 or 2 substituents selected from substituent group A.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d in the definition of substituent group A (with the proviso that the xe2x80x9cC1-6 alkyl groupxe2x80x9d in the definition of R4 is not included) is a straight or branched chain alkyl group having 1 to 6 carbons, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl or hexyl group; preferably a C1-3 alkyl group; and more preferably a methyl group.
The xe2x80x9cC1-6 alkyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d in the definition of substituent group A is a straight or branched chain alkyl group having 1 to 6 carbons substituted with 1 to 5 substituents, said substituents being selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group, for example, a chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, pentafluorobutyl, pentafluoropentyl, pentafluorohexyl, bromomethyl, bromoethyl, dibromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxyprbpyl, dihydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxydifluoromethyl, hydroxydifluoroethyl, hydroxytetrafluoropropyl, hydroxytetrafluorobutyl, hydroxytetrafluoropentyl, hydroxytetrafluorohexyl, hydroxychloroethyl, hydroxychloropropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, cyanohexyl, cyanodifluoromethyl, cyanodifluoroethyl, cyanotetrafluoropropyl, cyanotetrafluorobutyl, cyanotetrafluoropentyl, cyanotetrafluorohexyl, cyanohydroxyethyl, cyanohydroxypropyl, cyanohydroxybutyl, cyanohydroxypentyl, cyanohydroxyhexyl, methoxymethyl, methoxyethyl or the like.
A preferred xe2x80x9cC1-6 alkyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d is an alkyl group having 1 to 6 carbons substituted with 1 to 4 substituents (said substituents being selected from a halogen atom, a hydroxyl group and a cyano group). An alkyl group having 1 to 4 carbons substituted with 1 to 4 substituents (said substituents being selected from a fluorine atom, a chlorine atom, a hydroxyl group and a cyano group), for example, a fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, trichloromethyl, 2-chloroethyl, 3-chloropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1-hydroxy-1-methylethyl, 1-methyl-3-hydroxypropyl, 1-methyl-2-hydroxypropyl, 1-methyl-1-hydroxypropyl, or cyanomethyl group is more preferred. A trifluoromethyl or cyanomethyl group is most preferred.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d in the definitions of substituent group A and a substituent moiety of the substituent group A is a straight or branched chain alkoxy group having 1 to 6 carbons, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy or hexyloxy group. A preferred xe2x80x9cC1-6 alkoxy groupxe2x80x9d is an alkoxy group having 1 to 3 carbons and a methoxy or ethoxy group is more preferred.
The xe2x80x9cC1-6 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d is a straight or branched chain alkoxy group having 1 to 6 carbons substituted with 1 to 5 substituents, said substituents being selected from a halogen atom, a hydroxyl group and a cyano group, for example, a chloromethoxy, dichloromethoxy, trichloromethoxy, chloroethoxy, dichloroethoxy, trichloroethoxy, chloropentyloxy, chlorohexyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoropropoxy, tetrafluoropropoxy, fluoropentyloxy, fluorohexyloxy, trifluoropropoxy, tetrafluoropropoxy, bromomethoxy, bromoethoxy, bromopropoxy, bromobutoxy, bromopentyloxy, bromohexyloxy, hydroxyethyloxy, hydroxypropyloxy, dihydroxypropyloxy, hydroxybutyloxy, hydroxypentyloxy, hydroxyhexyloxy, hydroxyfluoroethoxy, hydroxydifluoroethoxy, hydroxyfluoropropoxy, hydroxytetrafluoropropoxy, hydroxytetrafluorobutoxy, hydroxytetrafluoropentyloxy, hydroxychloroethoxy, hydroxydichloroethoxy, cyanofluoroethoxy, cyanodifluoroethoxy, cyanofluoropropoxy, cyanotetrafluoropropoxy, cyanotetrafluorobutoxy, cyanotetrafluoropentyloxy, (hydroxymethyl)hydroxyethoxy, methoxymethoxy, or t-butoxymethoxy group.
A preferred xe2x80x9cC1-6 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d is an alkoxy group having 1 to 4 carbons substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group). An alkoxy group having 1 to 4 carbons substituted with 1 to 5 substituents (said substituents being selected from a fluorine atom, a chlorine atom and a hydroxyl group), for example, a chloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2-dichloroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 2,2,3,3-tetrafluoropropoxy, 2-hydroxyethyloxy, 3-hydroxypropyloxy, 4-hydroxybutyloxy, (1-ethyl-3-hydroxypropyl)oxy, (1-ethyl-2-hydroxypropyl)oxy, 2-hydroxy-1,1-difluoroethoxy, 4-hydroxy-2,2,3,3-tetrafluorobutoxy, or 1-(hydroxymethyl)-2-hydroxyethoxy group is more preferred. A trifluoromethoxy or tetrafluoropropoxy group is most preferred.
The xe2x80x9cC1-6 alkanoyl groupxe2x80x9d in the definition of substituent group A represents a straight or branched chain alkanoyl group having 1 to 6 carbons, for example, a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl or hexanoyl group. A preferred xe2x80x9cC1-6 alkanoyl groupxe2x80x9d is an alkanoyl group-having 1 to 3 carbons, and an acetyl group is more preferred.
The xe2x80x9cC2-6 alkanoyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d in the definition of substituent group A is a straight or branched chain alkanoyl group having 2 to 6 carbons substituted with 1 to 5 substituents, said substituents being selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group, for example, a hydroxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, cyanoacetyl, hydroxypropionyl, fluoropropionyl, difluoropropionyl, trifluoropropionyl, chloropropionyl, bromopropionyl, chlorobutyryl, fluorobutyryl, difluorobutyryl, trifluorobutyryl, fluorohydroxybutyryl, difluorohydroxybutyryl, cyanobutyryl, (hydroxymethyl)methylpropionyl, hydroxyvaleryl, cyanovaleryl, fluorovaleryl, hydroxyhexanoyl, or methoxyacetyl group.
A preferred xe2x80x9cC2-6 alkanoyl group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d is an alkanoyl group having 2 to 6 carbons substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group). An alkanoyl group having 2 to 4 carbons substituted with 1 to 3 substituents (said substituents are selected from a fluorine atom and a hydroxyl group), for example, a hydroxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, 2-hydroxypropionyl, 3-hydroxypropionyl, 2-hydroxybutyryl, 3-hydroxybutyryl, 4-hydroxybutyryl, or 2-methyl-2-hydroxypropionyl group is more preferred. A trifluoroacetyl group is most preferred.
The xe2x80x9cC1-6 alkanoyloxy groupxe2x80x9d in the definition of substituent group A is a straight or branched chain alkanoyloxy group having 1 to 6 carbons, for example, a formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy or hexanoyloxy group. A preferred xe2x80x9cC1-6 alkanoyloxy groupxe2x80x9d is an alkanoyloxy group having 1 to 3 carbons. A more preferred group is an acetoxy group.
The xe2x80x9cC2-6 alkanoyloxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d in the definition of substituent group A is a straight or branched chain alkanoyloxy group having 2 to 6 carbons substituted with 1 to 5 substituents, said substituents being selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group, for example, a hydroxyacetoxy, fluoroacetoxy, difluoroacetoxy, trifluoroacetoxy, cyanoacetoxy, hydroxypropionyloxy, fluoropropionyloxy, difluoropropionyloxy, trifluoropropionyloxy, chloropropionyloxy, bromopropionyloxy, hydroxybutyryloxy, chlorobutyryloxy, fluorobutyryloxy, difluorobutyryloxy, trifluorobutyryloxy, fluorohydroxybutyryloxy, difluorohydroxybutyryloxy, cyanobutyryloxy, (hydroxymethyl)methylpropionyloxy, hydroxyvaleryloxy, cyanovaleryloxy, fluorovaleryloxy, hydroxyhexanoyloxy or methoxyacetyloxy group.
A preferred xe2x80x9cC2-6 alkanoyloxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group, a cyano group and a C1-6 alkoxy group)xe2x80x9d is an alkanoyloxy group having 2 to 6 carbons substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group). An alkanoyloxy group having 2 to 6 carbons substituted with 1 to 4 substituents (said substituents are hydroxyl groups), for example, a hydroxyacetoxy, hydroxypropionyloxy, hydroxybutyryloxy, hydroxyvaleryloxy, or hydroxyhexanoyloxy group is more preferred. A hydroxyacetoxy or hydroxypropionyloxy group is most preferred.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d in the definition of R4 represents a straight or branched chain alkyl group having 1 to 6 carbons and the xe2x80x9cC1-6 alkyl group substituted with 1 to 5 substituentsxe2x80x9d in the definition of R4 represents a straight or branched chain alkyl group having 1 to 6 carbons substituted with 1 to 5 substituents which are the same or different halogen atoms. R4 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, bromomethyl, bromoethyl, dibromoethyl, bromopropyl, or the like. Preferably R4 is an alkyl group having 1 to 3 carbon atoms or an alkyl group having 1 to 3 carbon atoms substituted with 1 to 5 substituents (said substituents are fluorine atoms), for example methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl or the like. A methyl or trifluoromethyl group is more preferred.
The xe2x80x9cC2-6 alkenyl groupxe2x80x9d in the definition of substituent group A is a straight or branched chain alkenyl group having 2 to 6 carbons and one double bond, for example ethenyl, propenyl, methylpropenyl, ethylpropenyl, butenyl, methylbutenyl, ethylbutenyl, pentenyl, methylpentenyl, hexenyl or the like.
The xe2x80x9cC2-6 alkynyl groupxe2x80x9d in the definition of substituent group A is a straight or branched chain alkynyl group having 2 to 6 carbons and one triple bond, for example ethynyl, propynyl, methylpropynyl, ethylpropynyl, butynyl, methylbutynyl, ethylbutynyl, pentynyl, methylpentynyl, hexynyl, or the like.
The xe2x80x9cC3-6 cycloalkyl groupxe2x80x9d in the definition of substituent group A is a saturated aliphatic cyclic hydrocarbon group having 3 to 6 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
The xe2x80x9c(C3-6 cycloalkyl)C1-6 alkyl groupxe2x80x9d in the definition of substituent group A is a C1-6 alkyl group substituted with one C3-6 cycloalkyl group, for example, a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylhexyl group or the like.
Preferably, substituent group A is substituent group Al which comprises a C1-6 alkyl group, a C1-6 alkyl group substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a C1-6 alkanoyl group, a C2-6 alkanoyl group substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a C1-6 alkanoyloxy group, a C2-6 alkanoyloxy group substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a halogen atom, a hydroxyl group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group, and a group of formula xe2x80x94S(O)nR4 (wherein R4 represents a C1-6 alkyl group or a C1-6 alkyl group substituted with 1 to 5 substituents (said substituents are selected from halogen atoms), and n represents 0, 1 or 2).
More preferably, substituent group A is substituent group A2 which comprises a C1-3 alkyl group, a C1-4 alkyl group substituted with 1 to 4 substituents (said substituents are selected from a fluorine atom, a chlorine atom, a hydroxyl group and a cyano group), a C1-3 alkoxy group, a C1-4 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a fluorine atom, a chlorine atom and a hydroxyl group), a C1-3 alkanoyl group, a C2-4 alkanoyl group substituted with 1 to 3 substituents (said substituents are selected from a fluorine atom and a hydroxyl group), a C1-3 alkanoyloxy group, a C2-6 alkanoyloxy group substituted with 1 to 4 substituents (said substituents are hydroxyl groups), a halogen atom, a hydroxyl group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group, and a group of formula xe2x80x94S(O)nR4 (wherein R4 represents a C1-3 alkyl group, or a C1-3 alkyl group substituted with 1 to 5 substutituents (said substituents are fluorine atoms); and n represents 0, 1 or 2).
Most preferably, substituent group A is substituent group A3 which comprises a methyl group, a trifluoromethyl group, a cyanomethyl group, a trifluoromethoxy group, a tetrafluoropropoxy group, an acetyl group, an acetoxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group, a trifluoromethylthio group, a methanesulfonyl group and a trifluoromethanesulfonyl group.
When a moiety selected from substituent group A to A3 has substituents, a preferred number of substituents is 1 or 2.
Ar1 is, for example, a phenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, (trifluoromethyl)phenyl, chloro-fluorophenyl, bromofluorophenyl, fluoroiodophenyl, fluoro-(trifluoromethyl)phenyl, bromochlorophenyl, chloroiodophenyl, chloro(trifluoromethyl)phenyl, bromoiodophenyl, bromo-(trifluoromethyl)phenyl, iodo(trifluoromethyl)phenyl, dichlorophenyl, difluorophenyl, dibromophenyl, trifluorophenyl, or trichlorophenyl group.
Preferably, Ar1 is a phenyl group substituted with 1 to 3 substituents (said substituent is a fluorine atom, a chlorine atom or a trifluoromethyl group), for example, a 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 2,3-difluorophenyl, 2-fluoro-3-chlorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2,5-difluorophenyl, 2-fluoro-5-chlorophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, or 2,3,5-trifluorophenyl group.
More preferably, Ar1 is a phenyl group substituted with 1 or 2 substituents (said substituent is a fluorine atom, a chlorine atom or a trifluoromethyl group), for example, a 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, or 2-fluoro-4-(trifluoromethyl)phenyl group.
Still more preferably, Ar1 is a 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, or 2,4-difluorophenyl group.
Most preferably, Ar1 is a 2,4-difluorophenyl group.
Ar2 is, for example, a 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,4-naphthylene, 2,5-naphthylene, 2,6-naphthylene, 2-fluoro-1,4-phenylene, 3-chloro-1,4-phenylene, 2-chloro-1,4-phenylene, 3-chloro-1,4-phenylene, 2,6-difluoro-1,4-phenylene, or 2,6-dichloro-1,4-phenylene group.
Preferably, Ar2 is 1,4-phenylene, 1,4-phenylene substituted with 1 or 2 substituents, 2,6-naphthylene, or 2,6-naphthylene substituted with 1 or 2 substituents (said substituent is a fluorine atom or a chlorine atom). A 1,4-phenylene, or 1,4-phenylene group substituted with 1 or 2 substituents (said substituent is a fluorine atom or a chlorine atom) is more preferred and a 1,4-phenylene group is most preferred.
Preferably, X is a sulfur atom or a methylene group, and more preferably X is a sulfur atom.
R1 is, for example, a hydrogen atom, a methyl group or an ethyl group, preferably a C1-3 alkyl group, and most preferably a methyl group.
R2 is, for example, a hydrogen atom, a methyl group or an ethyl group, preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.
R3 is, for example, a benzyl, chlorobenzyl, fluorobenzyl, cyanobenzyl, nitrobenzyl, (trifluoromethyl)benzyl, naphthylmethyl, bromonaphthylmethyl, phenyl, tolyl, (trifluoromethyl)phenyl, hydroxymethylphenyl, hydroxyethylphenyl, cyanomethylphenyl, fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, pentafluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, cyanophenyl, carboxyphenyl, dicyanophenyl, chlorocyanophenyl, cyanofluorophenyl, nitrophenyl, (trifluoromethoxy)phenyl, (tetrafluoropropoxy)phenyl, acetylphenyl, (trifluoroacetyl)phenyl, carbamoylphenyl, methylthiophenyl, methylsulfinylphenyl, methylsulfonylphenyl, (trifluoromethyl)thiophenyl, (trifluoromethylsulfinyl)phenyl, (trifluoromethylsulfonyl)phenyl, carboxyphenyl, naphthyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, cyanonaphthyl, (tetrafluoropropoxy)naphthyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, methoxypyridyl, oxazolyl, isoxazolyl or thiazolyl group.
Preferably, R3 is a 6- to 10-membered aryl group, a 6- to 10-membered aryl group substituted with 1 to 5 substituents selected from substituent group A, a 5- or 6-membered heteroaryl group, or a 5- or 6-membered heteroaryl group substituted with 1 or 2 substituents selected from substituent group A. More preferably, R3 is a 6- to 10-membered aryl group, or a 6- to 10-membered aryl group substituted with 1 to 5 substituents selected from substituent group A. Yet more preferably R3 is a phenyl group substituted with 1 to 5 substituents selected from substituent group A or an unsubstituted phenyl group. Yet more and particularly preferably, R3 is a phenyl group substituted with 1 to 5 substituents selected from substituent group A1 or an unsubstituted phenyl group. Yet more and more particularly preferably, R3 is a phenyl group substituted with 1 to 5 substituents selected from substituent group A2 or an unsubstituted phenyl group. Still more preferably, R3 is a phenyl group substituted with 1 or 2 substituents selected from substituent group A3. Most preferably, R3 is a (tetrafluoropropoxy)phenyl, cyanophenyl, cyanomethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, (trifluoromethyl)phenyl, (trifluoromethoxy)phenyl, (trifluoromethylthio)phenyl, methylphenyl, chlorocyanophenyl, nitrophenyl, tetrafluorocyanophenyl, dicyanophenyl, acetylphenyl, acetoxyphenyl, fluorocyanophenyl, carbamoylphenyl, carboxyphenyl, hydroxyphenyl, (methanesulfonyl)phenyl, or (trifluoromethanesulfonyl)phenyl group.
The term xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d of compound (I) denotes a derivative of compound (I) having a protected hydroxyl group or the like which is capable of being cleaved by a chemical or biological process (e.g. by hydrolysis) on administration of the derivative to the body of a live animal to give the parent compound (I) or a salt thereof. Whether the derivative of compound (I) is such a prodrug can be easily determined. The derivative of compound (I) having a protected hydroxyl group or the like under investigation is administered orally or intravenously to a test animal such as a mouse or a rat and the body fluids of the test animal are thereafter studied. If the parent compound (I) or a salt thereof is detected in the body fluids of the test animal, the derivative under investigation is judged to be a prodrug of the compound (I). The compound (I) of this invention has a hydroxyl group and a triazole group, and an NH group when R2 of the compound (I) is a hydrogen atom.
It is possible to obtain a pharmaceutically acceptable prodrug using these functional groups. Examples of such prodrugs include, for example, prodrugs of which a hydroxyl or NH group is modified by an acyl group.
As used herein, the term xe2x80x9cacyl groupxe2x80x9d includes, for example an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aminoacyl group, phosphonyl group, or the like.
The xe2x80x9caliphatic acyl groupxe2x80x9d includes an alkanoyl group having 1 to 20 carbons, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, and icosanoyl. These aliphatic acyl groups may optionally have 1 to 3 multiple bonds and substituents such as a hydroxy group, a phosphoric group or a carboxyl group.
The xe2x80x9caromatic acyl groupxe2x80x9d includes an arylcarbonyl group having 7 to 11 carbons, for example, benzoyl, xcex1-naphthoyl or xcex2-naphthoyl. The aryl rings of these aromatic acyl groups may optionally have one or more substituents such as an alkyl group having 1 to 4 carbons, a halogen atom, an alkoxy group, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbons, a hydroxyalkyl group having 1 to 4 carbons, an alkylphosphonyl group having 1 to 4 carbons, or a carboxyalkyl group having 2 to 5 carbons.
The xe2x80x9calkoxycarbonyl group or aralkyloxycarbonyl groupxe2x80x9d includes an alkoxycarbonyl group having 2 to 20 carbons, for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or isobutoxycarbonyl; and includes an aralkyloxycarbonyl group having 8 to 20 carbons, for example benzyloxycarbonyl. These alkoxycarbonyl groups or the aryl ring of these aralkyloxycarbonyl groups may optionally have one or more substituents such as an alkyl group having 1 to 4 carbons, a halogen atom, an alkoxy group having 1 to 4 carbons, a hydroxyl group, a phosphoric group, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbons, a hydroxyalkyl group having 1 to 4 carbons, an alkylphosphonyl group having 1 to 4 carbons, or a carboxyalkyl group having 2 to 5 carbons.
The xe2x80x9camino acyl groupxe2x80x9d includes an amino acid group, for example, glycyl, alanyl, leucyl, phenylalanyl, glutamyl and asparaginyl; an aminoalkanoyl group having 1 to 10 carbons, for example, xcex2-alanyl, aminobutyryl or aminooctanoyl.
The xe2x80x9cphosphonyl groupxe2x80x9d includes phosphonyl, a monoalkylphosphonyl group wherein the alkyl part has 1 to 20 carbons, for example, methylphosphonyl, ethylphosphonyl, propylphosphonyl, butylphosphonyl, decylphosphonyl, or octadecylphosphonyl; a dialkylphosphonyl group wherein each alkyl part has 1 to 20 carbons, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl, dibutylphosphonyl, didecylphosphonyl, or dioctadecylphosphonyl; or the like.
A compound (I) or a pharmaceutically acceptable prodrug thereof has a basic triazole group and may form an acid addition salt. When R3 has a carboxyl group, a compound (I) or a pharmaceutically acceptable prodrug thereof may form a base addition salt. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d denotes these salts which are pharmaceutically acceptable.
The acid addition salts include inorganic acid salts, for example hydrochlorides, hydrobromides, sulfates, nitrates and phosphates; carboxylic acid salts, for example acetates, fumarates, maleates, oxalates, malonates, succinates, citrates and malates; sulfonate salts, for example methanesulfonates, ethanesulfonates, benzenesulfonates and toluenesulfonates; amino acid salts, for example glutamates and aspartates; and the like. Preferred salts are inorganic acid salts or carboxylic acid salts. More preferred salts are hydrochlorides, nitrates, fumarates, maleates or oxalates.
The base addition salts include alkali metal salts, for example lithium salts, sodium salts and potassium salts; alkaline earth metal salts, for example calcium salts and magnesium salts; ammonium salts; organic base salts, for example triethylamine salts, diisopropylamine salts and cyclohexylamine salts; and the like. Preferred salts are alkali metal salts and more preferred salts are sodium salts.
When a compound (I), a pharmaceutically acceptable prodrug thereof or a salt thereof is allowed to stand so that it is open to the atomosphere it may absorb water to form a hydrate. A compound (I), or a pharmaceutically acceptable prodrug thereof or a salt thereof may also absorb a solvent to give a solvate. The present invention encompasses these hydrates and solvates.
The carbon atom attached to Ar1 of the compound (I) is an asymmetric carbon, and optical isomers having this asymmetric carbon in S- and R-configuration therefore exist. When R1 is an alkyl group, the carbon atom attached to R1 is also an asymmetric carbon. The compound (I) can exist as diastereomers due to these asymmetric carbons. In addition, cis and trans isomers, based on the configuration of the two substituents of 1.3-dioxane ring of compound (I), also exist.
The formula (I) includes one of above described isomers as well as mixtures thereof.
The optical isomer described above can be isolated by a conventional optical resolution procedure or can be obtained by an asymmetric synthesis. A diastereomer and a cis or trans isomer can be isolated by a conventional isolation procedure such as fractional recrystallization or chromatography. Of these isolated isomers, preferred compounds (I) have the following formula (Ixe2x80x2). 
Preferred compounds of formula (I) of the present invention comprise:
(1) a compound wherein Ar1 is a phenyl group substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom, a chlorine atom and a trifluoromethyl group).
(2) a compound wherein Ar1 is a 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl or 2,4-difluorophenyl group.
(3) a compound wherein Ar1 is a 2,4-difluorophenyl group.
(4) a compound wherein Ar2 is a 1,4-phenylene group or a 1,4-phenylene group which is substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom and a chlorine atom), a 2,6-naphthylene group, or a 2,6-naphthylene group substituted with 1 or 2 substituents (said substituents are selected from a fluorine atom and a chlorine atom).
(5) a compound wherein Ar2 is a 1,4-phenylene group or a 1,4-phenylene group substituted with 1 or 2 substituents.
(6) a compound wherein Ar2 is a 1,4-phenylene group.
(7) a compound wherein X is a sulfur atom.
(8) a compound wherein X is a methylene group.
(9) a compound wherein R1 is a C1-3 alkyl group.
(10) a compound wherein R1 is a methyl group.
(11) a compound wherein R2 is a hydrogen atom.
(12) a compound wherein R3 is a C6-10 aryl group, a C6-10 aryl group substituted with 1 to 5 substituents selected from substituent group A, a 5- or 6-membered heteroaryl group, or a 5- or 6-membered heteroaryl group substituted with 1 or 2 substituents selected from substituent group A.
(13) a compound wherein R3 is a C6-10 aryl group or a C6-10 aryl group substituted with 1 to 5 substituents selected from substituent group A.
(14) a compound wherein R3 is a phenyl group substituted with 1 to 5 substituents selected from substituent group A or an unsubstituted phenyl group.
(15) a compound wherein R3 is a heteroaryl group or a heteroaryl group substituted with 1 or 2 substituents selected from substituent group A.
(16) a compound wherein R3 is a benzyl group or a benzyl group substituted with 1 or 2 substituents selected from substituent group A.
(17) a compound wherein R3 is a 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethylthio)phenyl, 4-methylphenyl, 3-chloro-4-cyanophenyl, 4-nitrophenyl, 2,3,5,6-tetrafluoro-4-cyanophenyl, 3,4-dicyanophenyl, 4-acetylphenyl, 4-acetoxyphenyl, 2-fluoro-4-cyanophenyl, 4-carbamoylphenyl, 4-carboxyphenyl, 4-hydroxyphenyl, 4-(methanesulfonyl)phenyl or 4-(trifluoromethanesulfonyl) phenyl group.
(18) a compound wherein substituent group A is substituent group A1 which comprises a C1-6 alkyl group, a C1-6 alkyl group substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a C1-6 alkoxy group, a C1-6 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a C1-6 alkanoyl group, a C2-6 alkanoyl group substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a C1-6 alkanoyloxy group, a C2-6 alkanoyloxy group substituted with 1 to 4 substituents (said substituents are selected from a halogen atom, a hydroxyl group and a cyano group), a halogen atom, a hydroxyl group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group and a group of formula xe2x80x94S(O)nR4 (wherein R4 represents a C1-6 alkyl group or a C1-6 alkyl group substituted with 1 to 5 substituents (said substituents are selected from halogen atoms), and n represents 0, 1, or 2). (19) a compound wherein substituent group A is substituent group A2 which comprises a C1-3 alkyl group, a C1-4 alkyl group substituted with 1 to 4 substituents (said substituents are selected from a fluorine atom, a chlorine atom, a hydroxyl group and a cyano group), a C1-3 alkoxy group, a C1-4 alkoxy group substituted with 1 to 5 substituents (said substituents are selected from a fluorine atom, a chlorine atom and a hydroxyl group), a C1-3 alkanoyl group, a C2-4 alkanoyl group substituted with 1 to 3 substituents (said substituents are selected from a fluorine atom and a hydroxyl group), a C1-3 alkanoyloxy group, a C2-6 alkanoyloxy group substituted with 1 to 4 substituents (said substituents are hydroxyl groups), a halogen atom, a hydroxyl group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group and a group of formula xe2x80x94S(O)nR4 (wherein R4 represents a C1-3 alkyl group, or a C1-3 alkyl group substituted with 1 to 5 substituents (said substituents are fluorine atoms), and n represents 0, 1, or 2).
(20) a compound wherein substituent group A is substituent group A3 which comprises a methyl group, a trifluoromethyl group, a cyanomethyl group, a trifluoromethoxy group, a tetrafluoropropoxy group, an acetyl group, an acetoxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, a carbamoyl group, a nitro group, a cyano group, a carboxyl group, a trifluoromethylthio group, a methanesulfonyl group and a trifluoromethanesulfonyl group.
Among compounds described in (1) to (20), a compound of which each substituent is optionally selected the groups specified in (1) to (20) is also preferred. Such preferred compounds are described in the following statements (21) and (22):
(21) a compound wherein Ar1 is a 2,4-difluorophenyl group; Ar2 is a 1,4-phenylene group; X is a sulfur atom; R3 is a C1-3 alkyl group; R2 is a hydrogen atom; R1 is a phenyl group substituted with 1 or 2 substituents selected from substituent group A3.
(22) a compound wherein Ar1 is a 2,4-difluorophenyl group; Ar2 is a 1,4-phenylene group; X is a sulfur atom; R1 is a methyl group; R2 is a hydrogen atom; R3 is a 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-(trifluoromethylthio)phenyl, 4-methylphenyl, 3-chloro-4-cyanophenyl, 4-nitrophenyl, 2,3,5,6-tetrafluoro-4-cyanophenyl, 3,4-dicyanophenyl, 4-acetylphenyl, 4-acetoxyphenyl, 2-fluoro-4-cyanophenyl, 4-carbamoylphenyl, 4-carboxyphenyl, 4-hydroxyphenyl, 4-(methanesulfonyl)phenyl or 4-(trifluoromethanesulfonyl)phenyl group.
When a compound (I) has two or more substituents selected from substituent groups A to A3, these substituents may be the same or different.
Examples of compound (I) of the present invention are exemplified in table 1. The present invention is not limited to these compounds.
In Table 1 the following abbreviations are used with the following meanings.
Me: methyl,
CN: cyano (attached via a carbon atom), Et: ethyl,
Ph: phenyl, 1,4-Ph: 1,4-phenylene, Np: naphthyl,
2,6-Np: 2,6-naphthylene, Pyr: pyridyl, Thz: thiazolyl,
Tet: tetra.
For example, exemplification compound number 1-1 has the following formula (Ia); 
exemplification compound number 14-4 has the following formula (Ib); 
and;
exemplification compound number 1-21 has the following formula (Ic). 
Of the exemplification compounds, preferred compounds are those of exemplification compound numbers:
1-1, 1-2, 1-3, 1-4, 1-9, 1-11, 1-21, 1-22, 2-1, 2-2, 2-3, 2-4, 2-9, 2-11, 2-21, 2-22, 2-25, 3-1, 3-2, 3-3, 3-4, 3-9, 3-11, 3-21, 3-22, 4-1, 4-2, 4-3, 4-4, 4-9, 4-11, 4-21, 4-22, 4-25, 5-1, 5-2, 5-3, 5-4, 5-9, 5-11, 5-21, 5-22, 6-1, 6-2, 6-3, 6-4, 6-9, 6-11, 6-21, 6-22, 7-1, 7-2, 7-3, 7-4, 7-9, 7-11, 7-21, 7-22, 8-1, 8-2, 8-3, 8-4, 8-9, 8-11, 8-21, 8-22, 9-1, 9-2, 9-3, 9-4, 9-9, 9-11, 9-21, 9-22, 10-1, 10-2, 10-3, 10-4, 10-9, 10-11, 10-21, 10-22, 11-1, 11-2, 11-3, 11-4, 11-9, 11-11, 11-21, 11-22, 13-1, 13-2, 13-3, 13-4, 13-9, 13-11, 13-21, 13-22, 14-1, 14-3, 15-1, 15-3, 16-1, 16-2, 16-3, 16-4, 16-9, 16-11, 16-21, 16-22, 17-1, 17-2, 17-3, 17-4, 17-9, 17-11, 17-21, 17-22, 18-1, 18-2, 18-3, 18-4, 18-9, 18-11, 18-21, 18-22, 19-1, 19-2, 24-1, 24-2, 25-1, 26-1, 27-1, 27-2, 27-3, 27-4, 27-9, 27-11, 27-21, 27-22, 28-1, 28-2, 28-3, 28-4, 28-9, 28-11, 28-21, 28-22, 29-1, 29-2, 29-3, 29-4, 29-9, 29-11, 29-21, 29-22, 40-1, 40-2, 41-1 and 41-2.
Of these compounds (I) more preferred compounds include:
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(2,2,3,3-tetrafluoropropoxy)benzanilide (exemplification compound number 1-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(2,2,3,3-tetrafluoropropoxy)-2-naphthoanilide (exemplification compound number 1-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(2,2,3,3-tetrafluoropropoxy)benzanilide (exemplification compound number 1-3),
4xe2x80x2-cyano-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-1),
4xe2x80x2-cyano-6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 2-2),
4xe2x80x2-cyano-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-3),
4xe2x80x2-cyano-6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 2-4),
4xe2x80x2-cyano-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzanilide (exemplification compound number 2-21),
4xe2x80x2-cyano-3-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-25),
4xe2x80x2-(cyanomethyl)-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 3-1),
4xe2x80x2-chloro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 4-1),
4xe2x80x2-chloro-6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 4-2),
4xe2x80x2-chloro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 4-3),
4xe2x80x2-chloro-6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 4-4),
4xe2x80x2-chloro-3-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 4-25),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-fluorobenzanilide (exemplification compound number 5-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-fluoro-2-naphthoanilide (exemplification compound number 5-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-fluorobenzanilide (exemplification compound number 5-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-fluoro-2-naphthoanilide (exemplification compound number 5-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 6-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)-2-naphthoanilide (exemplification compound number 6-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 6-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)-2-naphthoanilide (exemplification compound number 6-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethoxy)benzanilide (exemplification compound number 7-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethoxy)-2-naphthoanilide (exemplification compound number 7-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethoxy)benzanilide (exemplification compound number 7-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethoxy)-2-naphthoanilide (exemplification compound number 7-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethylthio)benzanilide (exemplification compound number 8-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethylthio)-2-naphthoanilide (exemplification compound number 8-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethylthio)benzanilide (exemplification compound number 8-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethylthio)-2-naphthoanilide (exemplification compound number 8-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-methylbenzanilide (exemplification compound number 9-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-methylbenzanilide (exemplification compound number 9-3),
4xe2x80x2-bromo-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 10-1),
4xe2x80x2-bromo-6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 10-2),
4xe2x80x2-bromo-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 10-3),
4xe2x80x2-bromo-6-[5-[3.-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 10-4),
3xe2x80x2-chloro-4xe2x80x2-cyano-4-[S-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 11-1),
3xe2x80x2-chloro-4xe2x80x2-cyano-6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 11-2),
3xe2x80x2-chloro-4xe2x80x2-cyano-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 11-3),
3xe2x80x2-chloro-4xe2x80x2-cyano-6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 11-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-nitrobenzanilide (exemplification compound number 13-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-nitrobenzanilide (exemplification compound number 13-3),
4xe2x80x2-cyano-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio)-1,3-dioxan-2-yl-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrafluoro]benzanilide (exemplification compound number 14-1),
4xe2x80x2-cyano-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrafluorobenzanilide (exemplification compound number 14-3),
3xe2x80x2,4xe2x80x2-dicyano-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 15-1),
3xe2x80x2,4xe2x80x2-dicyano-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 15-3),
4xe2x80x2-acetyl-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 16-1),
4xe2x80x2-acetyl-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 16-3),
4xe2x80x2-acetoxy-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 17-1),
4xe2x80x2-acetoxy-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 17-3),
4xe2x80x2-cyano-2xe2x80x2-fluoro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 18-1),
4xe2x80x2-cyano-2xe2x80x2-fluoro-6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 18-2),
4xe2x80x2-cyano-2xe2x80x2-fluoro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 18-3),
4xe2x80x2-cyano-2xe2x80x2-fluoro-6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-2-naphthoanilide (exemplification compound number 18-4),
4xe2x80x2-carbamoyl-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 24-1),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-iodobenzanilide (exemplification compound number 25-1),
4-[N-[4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoyl]amino]benzoic acid (exemplification compound number 26-1),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-hydroxybenzanilide (exemplification compound number 27-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-hydroxy-2-naphthoanilide (exemplification compound number 27-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-hydroxybenzanilide (exemplification compound number 27-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-hydroxy-2-naphthoanilide (exemplification compound number 27-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(methanesulfonyl)benzanilide (exemplification compound number 28-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(methanesulfonyl)-2-naphthoanilide (exemplification compound number 28-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(methanesulfonyl)benzanilide (exemplification compound number 28-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(methanesulfonyl)-2-naphthoanilide (exemplification compound number 28-4),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethanesulfonyl)benzanilide (exemplification compound number 29-1),
6-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethanesulfonyl)-2-naphthoanilide (exemplification compound number 29-2),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethanesulfonyl)benzanilide (exemplification compound number 29-3),
6-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethanesulfonyl)-2-naphthoanilide (exemplification compound number 29-4),
2xe2x80x2,4xe2x80x2-dichloro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 40-1),
2xe2x80x2,4xe2x80x2-dichloro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 40-2),
2xe2x80x2-chloro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 41-1), and
2xe2x80x2-chloro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 41-2).
Of these compounds (I), still more preferred compounds include:
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(2,2,3,3-tetrafluoropropoxy)benzanilide (exemplification compound number 1-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(2,2,3,3-tetrafluoropropoxy)benzanilide (exemplification compound number 1-3),
4xe2x80x2-cyano-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-1),
4xe2x80x2-cyano-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-3),
4xe2x80x2-chloro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 4-1),
4xe2x80x2-chloro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 4-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-fluorobenzanilide (exemplification compound number 5-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-fluorobenzanilide (exemplification compound number 5-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 6-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 6-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethoxy)benzanilide (exemplification compound number 7-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethoxy)benzanilide (exemplification compound number 7-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethylthio)benzanilide (exemplification compound number 8-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethylthio)benzanilide (exemplification compound number 8-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-methylbenzanilide (exemplification compound number 9-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-methylbenzanilide (exemplification compound number 9-3),
3xe2x80x2-chloro-4xe2x80x2-cyano-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 11-1),
3xe2x80x2-chloro-4xe2x80x2-cyano-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 11-3),
4xe2x80x2-cyano-2xe2x80x2-fluoro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 18-1),
4xe2x80x2-cyano-2xe2x80x2-fluoro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 18-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-hydroxybenzanilide (exemplification compound number 27-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-hydroxybenzanilide (exemplification compound number 27-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(methanesulfonyl)benzanilide (exemplification compound number 28-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(methanesulfonyl)benzanilide (exemplification compound number 28-3),
4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethanesulfonyl)benzanilide (exemplification compound number 29-1),
4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethanesulfonyl)benzanilide (exemplification compound number 29-3),
2xe2x80x2,4xe2x80x2-dichloro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 40-1),
2xe2x80x2,4xe2x80x2-dichloro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 40-2),
2xe2x80x2-chloro-4-[5-[[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 41-1), and
2xe2x80x2-chloro-4-[5-[3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]-4xe2x80x2-(trifluoromethyl)benzanilide (exemplification compound number 41-2).
Of these compounds (I) particularly preferred compounds include:
4xe2x80x2-cyano-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-1),
4xe2x80x2-cyano-4-[trans-5-[(2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 2-3),
4xe2x80x2-chloro-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl)benzanilide (exemplification compound number 4-1), and
4xe2x80x2-chloro-4-[trans-5-[(2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyl]-1,3-dioxan-2-yl]benzanilide (exemplification compound number 4-3),
The compound (I) of the present invention can be easily prepared by Method A or B illustrated below.
[Method A]
Method A is a process for preparation of compound (I) and is illustrated by the following reaction scheme. 
In the above reaction scheme Ar1, Ar2, X, R1, R2 and R3 have the same meanings as described above.
In Method A, the reaction of a carboxylic acid compound of formula (II) or a reactive derivative thereof with an amine compound of formula (III) to give an amide compound of formula (IV) (Step A-1) is followed by the reaction of the compound of formula (IV) with a compound of formula (V) to afford a compound of formula (I) (Step A-2). Each step of Method A is described below.
Step A-1 is a process for preparation of an amide compound of formula (IV) and comprises the reaction of a carboxylic acid compound of formula (II) or a reactive derivative thereof with an amine compound of formula (III) in an inert solvent.
The carboxylic acid compound of formula (II) is commercially available or can be prepared by techniques well known to those skilled in the art. A carboxylic acid compound of formula (II), for example, can be obtained by methyl-esterification reaction of a dicarboxylic acid compound (Ar2(CO2H)2), reduction of one ester group of the esterified compound (Ar2(CO2CH3)2) with Red-Al or the like, oxidation of the product with activated manganese dioxide, followed by hydrolysis of the formyl-ester compound (Ar2(CO2CH3) (CHO)).
The amine compound of formula (III) is also commercially available or can be prepared by techniques known to those skilled in the art.
The solvent used in Step A-1 is not particularly limited provided that it has no adverse effect on the reaction and that it dissolves the starting materials to some extent. Such solvents include aprotic solvents, for example, halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether or tetrahydrofuran; nitrites such as acetonitrile; heteroaryl bases containing one or more nitrogen atoms such as pyridine; or mixtures thereof. Of these solvents, preferred solvents include halogenated hydrocarbons, ethers and heteroaryl bases containing one or more nitrogen atoms. Dichloromethane, tetrahydrofuran or pyridine is particularly preferred.
When the carboxylic acid compound of formula (II) is used in Step A-1, a coupling reagent can be used. Said coupling reagent is not particularly limited provided that it can usually be used as a coupling reagent in organic synthesis. Examples of such reagents include carbodiimides such as dicyclohexylcarbodiimide.
When the reactive derivative of the carboxylic acid compound is used in Step A-1, said carboxylic acid compound of formula (II) is converted to a reactive compound of formula OHC-Ar2-COZ (wherein Z represents a leaving group, for example, a halogen atom, an azido group, a cyano group, a C1-6 alkylsulfonyloxy group such as a methanesulfonyloxy group, a halogeno-C1-6-alkylsulfonyloxy group such as a trifluoromethanesulfonyloxy group, a C1-6 alkanoyloxy group such as a pivaloyloxy group, or a heteroaryl group such as an imidazolyl group or a triazolyl group) or a compound of formula (OHC-Ar2-CO)2O. The reaction of Step A-1 can be accomplished by the reaction of said reactive derivative of the carboxylic acid compound of formula (II) with a compound of formula (III) in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 4-(N,N-dimethylamino)pyridine.
Reagents leading to a reactive derivative of a carboxylic acid compound of formula (II) include, for example, thionyl halides such as thionyl chloride; reactive phosphoric acid derivatives such as phosphorus oxychloride or diphenylphosphoryl azide; acid chlorides such as pivaloyl chloride, oxalyl chloride and the like; reactive sulfonic acid derivatives such as methanesulfonyl chloride or trifluoromethanesulfonic acid anhydride; reactive carbonate derivatives such as phosgene, trichloromethyl chloroformate, triphosgene or 1,1xe2x80x2-carbonyldiimidazole; reactive oxalic acid derivatives such as oxalyl chloride; preferably thionyl chloride or oxalyl chloride. The amount of the reagent is in the range of from 1 to 10 equivalents of the amount of the carboxylic acid compound of formula (II), preferably in the range of 1 to 2 equivalents.
The amount of the amine compound of formula (III) is in the range from 0.5 to 2 molar equivalents of the amount of the carboxylic acid compound of formula (II) or the reactive derivative thereof, preferably in the range of 0.9 to 1.2 molar equivalents.
The reaction temperature of Step A-1 depends on various factors such as the starting material, the reagent and the solvent and is usually between xe2x88x9220xc2x0 C. and the boiling point of the reaction solvent, preferably between 0xc2x0 C. and room temperature.
The reaction time of Step A-1 depends on various factors such as the starting material, the reagent, the solvent and the reaction temperature. It is usually from 10 minutes to 24 hours, preferably from 1 to 2 hours.
After the reaction of Step A-1, the desired compound (IV) is isolated from the reaction mixture according to conventional techniques. For example, the reaction mixture, or the residue obtained by concentration of the reaction mixture, is partitioned between water and an organic solvent immiscible with water; the organic layer is then washed with water and then concentrated to afford the desired compound.
Step A-2 can be accomplished by the reaction of an aldehyde compound of formula (IV) with an alcohol compound of formula (V) in the presence of an acetalization reagent in an inert solvent, water produced during the reaction of Step A-2 being removed from the reaction mixture during said reaction.
In Step A-2, a salt of alcohol compound (V) or a compound of formula (VI) (wherein Ar1, R1 and X have the same meanings as described above; and R7 represents a C1-6 alkyl group or a C6-14 aryl group) can be also used as a starting material instead of an alcohol compound of formula (V). 
The xe2x80x9cC1-6 alkyl groupxe2x80x9d in the definition of R7 includes a straight or branched chain alkyl group having 1 to 6 carbons, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, preferably a straight or branched chain alkyl group having 1 to 4 carbons.
The xe2x80x9cC6-14 aryl groupxe2x80x9d includes an aromatic hydrocarbon group having 6 to 14 carbons, for example a phenyl group, an indenyl group, a naphthyl group or an anthracenyl group, preferably a phenyl group. Said xe2x80x9caryl groupxe2x80x9d may optionally be fused to a cycloalkyl group having 3 to 10 carbons, for example a 2-indanyl group.
Of these groups, R7 is preferably a phenyl group.
The alcohol compound of formula (V) can be prepared by the same procedure as or a similar procedure to that disclosed in the specifications of Japanese Patent Application Publication Nos. Hei-8-333350 and Hei-11-80135.
The compound of formula (VI) can be obtained as an intermediate in the process for preparation of the alcohol compound of formula (V) described in the above specifications. A salt of the alcohol compound of formula (V) can be obtained by removal of the protecting group of the compound of formula (VI).
The two primary hydroxyl groups of the alcohol compound of formula (V) may be optionally protected with a tri(C1-6 alkyl)silyl group, which consists of a silicon atom substituted with three C1-6 alkyl groups, for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl or t-butyldimethylsilyl, and a trimethylsilyl group is a preferred group.
The amount of the alcohol compound of formula (V) is in the range from 0.5 to 2 molar equivalents of the amount of the aldehyde compound of formula (IV), preferably from 0.9 to 1.2 molar equivalents.
The solvent used in Step A-2 is not particularly limited provided that it has no adverse effect on the reaction and that it dissolves the starting materials to some extent. Such solvents include aprotic solvents, for example, halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether or tetrahydrofuran; and the like. Preferred solvents include halogenated hydrocarbons or ethers, and dichloromethane or tetrahydrofuran is particularly preferred.
Examples of the acetalization reagent used in Step A-2 include inorganic acids such as hydrogen chloride, sulfuric acid or nitric acid; Lewis acids such as boron trifluoride, zinc chloride, magnesium bromide, titanium tetrachloride or aluminum chloride; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or trifluoromethanesulfonic acid; carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid or citric acid; and silylating reagents such as chlorotrimethylsilane or trimethylsilyl trifluoromethanesulfonate; preferably sulfonic acids; and most preferably p-toluenesulfonic acid.
The amount of the acetalization reagent is in the range from 1 to 3 molar equivalents of the amount of the alcohol compound of formula (V). When an aldehyde compound has a basic group, it is required to use an acid, the amount of which is an equal equivalent of the amount of said basic group.
The water produced during the reaction is removed by azeotropic distillation of the reaction solvent, by evaporation under reduced pressure, or by using a dehydrating reagent such as molecular sieves.
The reaction temperature of Step A-2 depends on various factors such as the acetalization reagent, the starting material and the solvent. It is usually between 0xc2x0 C. and the boiling point of the reaction solvent, preferably between 5xc2x0 C. and 40xc2x0 C.
The reaction time of Step A-2 depends on various factors such as the acetalization reagent, the starting material, the solvent and the reaction temperature. It is usually from 0.5 to 24 hours, preferably from 1 to 5 hours.
After the reaction of Step A-2, the reaction mixture is neutralized with aqueous sodium bicarbonate solution or the like and then the desired compound of formula (I) is isolated from the reaction mixture according to conventional techniques. For example, the reaction mixture, or the residue obtained by concentration of the reaction mixture, is partitioned between water and an organic solvent immiscible with water, and the organic layer is then washed with water and then concentrated to afford the desired product.
The desired product (I) obtained thus, if necessary, can be further purified by conventional procedures such as recrystallization, reprecipitation or chromatography.
In addition, when the product of Step A-2 has a protecting group, said product can be converted to the desired compound (I) by removal of the protecting group.
The reaction conditions for the removal of the protecting group depend on the protecting group. The removal reaction can be carried out by conventional procedures known to those skilled in the art (see, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Edition, Ed. by T. W. Greene and P. G. M. Wuts, 1991, John Wiley and Sons, Inc. or the like).
[Method B]
Method B is another process for preparation of compound (I) and is illustrated by the following reaction scheme. 
In the above reaction scheme, Ar1, Ar2, X, R1, R2 and R3 have the same meanings as described above; and R8 represents a C1-6 alkyl group or a C6-14 aryl group.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d in the definition of R8 includes a straight or branched chain alkyl group having 1 to 6 carbons, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, preferably a straight or branched chain alkyl group having 1 to 4 carbons.
The xe2x80x9cC6-14 aryl groupxe2x80x9d includes an aromatic hydrocarbon group having 6 to 14 carbons, for example a phenyl group, an indenyl group, a naphthyl group or an anthracenyl group, preferably a phenyl group.
Of these groups, R8 is preferably a methyl group.
In Method B, reaction of the alcohol compound of formula (V) with the compound of formula (VII) in the presence of an acetalization reagent in an inert solvent, using a similar procedure to that described in Step A-2, where water produced during the reaction is removed from the reaction mixture to give the compound of formula (VIII) (Step B-1), is followed by reaction of the compound of formula (VIII) with the amine compound of formula (III) in the presence of an activating agent in an inert solvent to afford the compound of formula (I) (Step B-2).
Step B-1 is a process for preparation of the dioxane compound of formula (VIII) and is accomplished by the reaction of the alcohol compound of formula (V) with the aldehyde compound of formula (VII) in the presence of an acetalization reagent in an inert solvent, water produced during the reaction being removed from the reaction mixture during said reaction.
The aldehyde compound of formula (VII) is commercially available or can be prepared by techniques well known to those skilled in the art. The aldehyde compound of formula (VII) can, for example, be obtained by methyl esterification of a dicarboxylic acid compound (Ar2(CO2H)2), reduction of one ester group of the esterified compound (Ar2(CO2CH3)2) with Red-Al or the like, followed by oxidation of the product with activated manganese dioxide.
This step can be accomplished using a similar procedure to that described in Step A-2.
Step B-2 can be accomplished by reaction of the compound of formula (VIII) with the amine compound of formula (III) in the presence of an activating reagent in an inert solvent.
The solvent used in Step B-2 is not particularly limited provided that it has no adverse effect on the reaction and that it dissolves the starting materials to some extent. Such solvents include aprotic solvents, for example, halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether or tetrahydrofuran; or mixtures thereof. Of these solvents, preferred solvents include aromatic hydrocarbons or halogenated hydrocarbons, and toluene is particularly preferred.
The activating reagent used in Step B-2 is not particularly limited provided that it can usually be used as a reagent for converting an ester to an amide in organic synthesis. Examples of such activating reagents include (lower alkyl)aluminiums such as trimethylaluminium or triethylaluminium; alkali metal cyanides such as sodium cyanide; hydroxy aromatic heterocyclic compounds containing one or more nitrogen atoms such as 2-hydroxypyridine; bases such as sodium methoxide or butyllithium; or halogenated borons such as boron tribromide. Of these activating agents, (lower alkyl)aluminiums are preferred and trimethylaluminium is particularly preferred.
The amount of the activating reagent used in Step B-2 is in the range from 1 to 5 molar equivalents of the amount of the ester compound of formula (VIII) and preferably from 1.5 to 3.0 molar equivalents.
The amount of the amine compound of formula (III) is in the range of from 0.5 to 5 molar equivalents of the amount of ester compound of formula (VIII), preferably from 0.9 to 2.5 molar equivalents.
The reaction temperature of Step B-2 depends on various factors such as the activating reagent, the starting material and the solvent. It is usually between room temperature and the boiling point of the reaction solvent, preferably between 50xc2x0 C. and 90xc2x0 C.
The reaction time of Step B-2 depends on various factors such as the activating reagent, the starting material, the solvent and the reaction temperature. It is usually from 0.5 to 24 hours, preferably from 1 to 5 hours.
After the reaction of Step B-2, to the reaction mixture is added aqueous sodium bicarbonate solution or the like in order to decompose the activating reagent, and then the desired compound (I) is isolated from the reaction mixture according to conventional techniques. For example, the reaction mixture, or the residue obtained by concentration of the reaction mixture, is partitioned between water and an organic solvent immiscible with water, and the organic layer is washed with water and then concentrated to afford the desired product.
The desired product of formula (I) thus obtained can, if necessary, be further purified by conventional procedures such as recrystallization, reprecipitation or chromatography.
In addition, when the product of Step B-2 has a protecting group, said product can be converted to the desired compound (I) by removal of the protecting group using a similar technique to that described in Method A.
Pharmaceutically acceptable prodrugs of compound (I) can be prepared by conventional techniques known to those skilled in the art. Of these pharmaceutically acceptable prodrugs, various acyl derivatives can be obtained by acylation of the hydroxyl group of compound (I) using conventional procedures.
The compound (I) or the pharmaceutically acceptable prodrug obtained above can be converted to a pharmaceutically acceptable salt by treating with an acid or a base in a solvent.
The solvents employed are not particularly limited and include, for example, aromatic hydrocarbons such as benzene; halogenated hydrocarbons such as dichloromethane or chloroform; ethers such as ether, tetrahydrofuran or dioxane; esters such as ethyl acetate; alcohols such as methanol or ethanol; ketones such as acetone; nitriles such as acetonitrile; hydrocarbons such as hexane or cyclohexane; or mixtures thereof.
The acids employed are not particularly limited provided that they are pharmaceutically acceptable acids. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid; carboxylic acids such as acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid or malic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid; or amino acids such as glutamic acid or aspartic acid.
The bases employed are not particularly limited provided that they are pharmaceutically acceptable bases. Examples of such bases include alkali metal (such as lithium, sodium or potassium) hydroxides or carbonates; alkaline earth metal (such as calcium or magnesium) hydroxides or carbonates; ammonia; organic amines such as triethylamine, diisopropylamine or cyclohexylamine.
The desired salt can usually be isolated from the solution of the compound (I) and the acid or the base as crystals or a powder, by adding a solvent which does not dissolve said salt to the solution containing said salt as a precipitate or by evaporation of the solvent of the solution containing said salt.
The compounds (I) and pharmaceutically acceptable salts thereof exhibit excellent antifungal activity against many eumycetes. Examples of eumycetes include Candida species, Aspergillus species, Cryptococcus species, Mucor species, Histoplasma species, Blastomyces species, Coccidioides species, Paracoccidioides species, Trichophyton species, Epidermophyton species, Microsporum species, Malassezia species, Psuedallescheria species, Sporothrix species, Rhinosporidium species, Fonsecaea species, Wangiella species, Phialophora species, Exophiala species, Cladosporium species, Alternaria species, Aureobasidium species, Chaetomium species, Curvularia species, Drechslera species, Mycocentrospora species, Phoma species, Hendersonula species, Scytalidium species, Corynespora species, Leptospheria species, Madurella species, Neotestudina species, Scedosporium species, Pyrenochaeta species, Geotrichum species, Trichosporon species, Chrysosporium species, Coprinus species, Schizophylum species, Pneumocystis species, Conidiobolus species, Basidiobolus species, Paecilomyces species, Penicillium species, Acremonium species, Fusarium species, Scopulariopsis species, Saccharomyces species, Cephalosporium species, Loboa species, Rhizopus species, Rhizomucor species or Absidia species.
The pharmaceutically acceptable prodrug of compound (I) produces the compound (I) or a salt thereof, which exhibits excellent antifungal activity, by a chemical or biological cleavage reaction (hydrolysis or the like) in the body of a human or animal. The compounds (I), pharmaceutically acceptable prodrugs thereof and pharmaceutically acceptable salts thereof can be used as a medicament, preferably as an antifungal agent. The compound (I), pharmaceutically acceptable prodrug thereof or salt thereof can be administered by itself or as a mixture of it with pharmaceutically acceptable carrier(s) including excipient(s), diluent(s), and the like in dosage forms such as tablets, capsules, granules, powders, syrups or the like for oral administration or in dosage forms such as injections or the like for parenteral administration and in ointments for topical administration.
The pharmaceutical formulations can be prepared in a known procedure using carriers such as excipients, binders, disintegrants, lubricants, stabilizers, corrigents, suspending agents, diluents, and solvents for formulation.
Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, xcex1-starch, dextrin or carboxymethylstarch, cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate or magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate, sulfates such as calcium sulfate, and the like.
Examples of binders include excipients such as those described above; gelatin; polyvinylpyrrolidone; macrogol; and the like.
Examples of disintegrants include excipients such as those described above, chemically modified starch or cellulose derivatives such as sodium cross-carmellose, sodium carboxymethylstarch, cross-linked polyvinylpyrrolidone and the like.
Example of lubricants include talc; stearic acid; metal stearate derivatives such as calcium stearate or magnesium stearate; colloidal silica; veegum; waxes such as beeswax or spermaceti; boric acid; glycol; carboxylic acids such as fumaric acid or adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid derivatives such as silicic acid anhydride or silicic acid hydrate; starch derivatives such as those described above in relation to excipients, and the like.
Examples of stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben or propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol or cresol; thimerosal; acetic anhydride, sorbic acid and the like.
Examples of corrigents include sweeteners, souring agents, flavoring agents and the like commonly used for the purpose.
Examples of suspending agents include polysorbate 80, sodium carboxymethylcellulose and the like.
Examples of solvents for formulation include water, ethanol, glycerin and the like.
The dose of the compound (I), pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof will vary depending on a variety of factors such as the age, symptoms and the like of the patient. A suitable (i.e. effective) dosage level for oral administration is from 1 mg (preferably 5 mg) per day and per time as a lower limit to 2000 mg (preferably 1000 mg) per day and per time as an upper limit for an adult. A suitable dosage level for intravenous administration is from 0.1 mg (preferably 0.5 mg) per day per time as a lower limit to 600 mg (preferably 500 mg) per day and per time as an upper limit for an adult. The compound (I), pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof can be administered either a single unit dosage, or if desired, the dosage may be divided into convenient subunits administered from one to six times throughout the day depending on the symptoms of the patient, (human or animal).